The application of nanotechnology in the medical field is called nanomedicine. Nowadays, this new branch of science is a point of interest for many investigators due to the important advances in which we assisted in recent decades, in particular for cancer treatment. Cancer nanomedicine has been applied in different fields such as drug delivery, nanoformulation and nanoanalytical contrast reagents. Nanotechnology may overcome many limitations of conventional approaches by reducing the side effects, increasing tumor drug accumulation and improving the efficacy of drugs. In the last two decades, nanotechnology has rapidly developed, allowing for the incorporation of multiple therapeutics, sensing and targeting agents into nanoparticles (NPs) for developing new nanodevices capable to detect, prevent and treat complex diseases such as cancer.In this review, we describe the main drug nanoformulations based on different types of organic NPs, the advantages that the new formulations present in comparison with their free drug counterparts and how nanodrugs have improved clinical care. We subdivided them into four main groups: polymeric NPs, liposomes, micelles and exosomes, a small subgroup that has only recently been used in clinical trials.The application of nanotechnology to pharmaceutical science has allowed us to build up nanosystems based on at least two stage vectors (drug/nanomaterial), which often shown better pharmacokinetics (PK), bioavailability and biodistribution. As a result of these advantages, the nanomaterials accumulate passively in the tumor (due to the enhanced permeability and retention, effect, EPR), thereby decreasing the side effects of free drug. Recently, many new drug formulations have been translated from bench to bedside.It is important to underline that the translation of nanomedicines from the basic research phase to clinical use in patients is not only expensive and time-consuming, but that it also requires appropriate funding. After many years spent in the design of innovative nanomaterials, it is now the time for the research to take into consideration the biological obstacles that nanodrugs have to overcome. Barriers such as the mononuclear phagocyte system, intratumoral pressure or multidrug resistance are regularly encountered when a cancer patient is treated, especially in the metastatic setting.
We synthesized, characterized and tested in a panel of cancer cell lines, nine new bipyridine gold(III) dithiocarbamate-containing complexes. In vitro studies demonstrated that compounds 1, 2, 4, 5, 7 and 8 were the most cytotoxic in prostate, breast, ovarian cancer cell lines and in Hodgkin lymphoma cells with IC50 values lower than the reference drug cisplatin. The most active compound 1 was more active than cisplatin in ovarian (A2780cis and 2780CP-16) and breast cancer cisplatin-resistant cells. Compound 1 determined an alteration of the cellular redox homeostasis leading to increased ROS levels, a decrease in the mitochondrial membrane potential, cytochrome-c release from the mitochondria and activation of caspases 9 and 3. The ROS scavenger NAC suppressed ROS generation and rescued cells from damage. Compound 1 resulted more active in tumor cells than in normal human Mesenchymal stromal cells. Gold compounds were active independent of p53 status: exerted cytotoxic effects on a panel of non-small cell lung cancer cell lines with different p53 status and in the ovarian A2780 model where the p53 was knocked out. In conclusion, these promising results strongly indicate the need for further preclinical evaluation to test the clinical potential of these new gold(III) complexes.
The epidermal growth factor receptor inhibitor (EGFRIs) treatments are commonly associated with the development of adverse skin effects. This study aims to investigate the lipid composition change in sebum during cetuximab-based treatment in an attempt to identify specific metabolic signatures useful in predicting the occurrence of severe skin toxicity. Sebum from 30 metastatic colorectal cancer (mCRC) patients was collected at three time points during the targeted therapy by the application of Sebutape® on the forehead, and the major lipid classes were analyzed and quantified by 1H-NMR. Univariate analysis was performed to reveal significant alterations among patients in sebum production as well as lipid composition and over the course of cetuximab therapy. A transient but significant decrease in sebum production associated with a reduction in the relative content of triglycerides (TG) and squalene (SQ) was found to be induced by cetuximab administration. The reduction of these two lipid classes was also found to be associated with the severity of skin rash experienced by patients. The results of this study indicate that cetuximab-based treatment can reduce sebum gland activity, leading to an overall decrease in sebum production and the induction of specific modifications to its composition. The extent of the loss of skin barrier function may be important for determining the severity of skin toxicity development.
The cDNA for human ciliary neuronotrophic factor (CNTF) has been cloned into an expression vector under the control of the T7 promoter. The BL21 strain of E. coli was transformed with this vector. Human CNTF accounted for about 30% of the total bacterial protein after induction with isopropyl-B-D-thiogalactopyranoside. This human CNTF was purified to homogeneity from inclusion bodies by a combination of ion exchange chromatography and reverse-phase high performance liquid chromatography. The amino-terminal amino acid sequence of the purified protein was identical to the deduced amino acid sequence; however, the methionyl residue has been removed. On SDS-PAGE gels, human CNTF displayed a molecular weight of about 24 kDa, in accord with its deduced molecular mass; a pI of 5.8 indicates the acidic nature of the molecule. A proposed structure for human CNTF includes major alpha helical regions. The ED50 of purified human CNTF was approximately 30 pM, using cultured embryonic day 10 chicken dorsal root ganglion neurons; no activity was observed with neurons from embryonic day 8 ganglia. Polyclonal antibodies prepared against both a synthetic peptide of CNTF and the entire human CNTF protein recognized a single 24 kDa band on Western blots, corresponding to human CNTF. However, only the antibodies against intact CNTF blocked its biological activity. This represents the first molecular expression and purification of human CNTF.
BACKGROUND: Mutation of IDH1 gene is a prognostic factor and a diagnostic hallmark of gliomas. Mutant IDH1 enzyme can convert α-KG into 2-Hydroxyglutarate(2HG); mutated gliomas have elevated amounts of intracellular 2HG. We analyzed 2HG concentration in plasma and urine in glioma patients(PTS) to identify a biomarker of IDH1 gene mutation METHODS: All PTS had a prior histological confirmation of glioma, a recent brain MRI (within 2 weeks) showing the neoplastic lesions. The exclusion criteria were any chemotherapy performed within 28 days prior, other neoplastic and metabolic diseases. Plasma and urine samples were taken from all PTS and 2HG concentrations determined by liquid chromatography tandem mass spectrometry; Mann-Whitney test was used to test for differences in metabolite concentrations. ROC curve was used to evaluate the cut off value of 2HG biomarker. RESULTS: 84 PTS were enrolled: 38 with IDH1 mutated and 46 IDH1 wild-type. Among PTS with mutant IDH1 we had 21 high-grade gliomas (HGG) and 17 low-grade gliomas (LGG); among PTS with IDH1 wild-type we had 35 HGG and 11 LGG. In all PTS we analyzed the mean 2HG concentration in plasma (P_2HG), in urine (U_2HG) and the ratio between P_2HG and U_2HG (R_2HG). We found an important significant difference in R_2HG between PTS with and without IDH1 mutation: 24.9 versus 15.3, respectively. The optimal cut-off value of R_2HG to identify glioma PTS with and without IDH1 mutation was 19 with sensitivity (S) 63%, specificity (SP) 76% and accuracy (A) 70%.; in only PTS with HGG the optimal cut-off value was 20 (S 76%, SP 89%, A 84%, PPV 80%, NPV 86%). No association between the grade or size of tumor and R_2HG were found. In 7 out of 7 HGG PTS, we found a correlation between R_2HG value and response to treatment. CONCLUSIONS: By analyzing the R_2HG derived from individual plasma and urine 2HG levels is possible discriminate glioma PTS with and without IDH1 mutation. A larger samples need to be analyzed to investigate this method to monitor treatment efficacy.
Background: Thyroid cancer is the most common endocrine neoplasia and represents approximately 1.5% to 2.1% of all cancers diagnosed annually worldwide. Iodine Refractory Differentiated Thyroid Carcinoma (RR-DTC) and advanced/metastatic medullary thyroid carcinoma are relatively uncommon yet prognostically significant thyroid cancers. Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers, including thyroid cancer. Many Multi-Kinase Inhibitors (MKIs) which are now FDA-/EMA approved for thyroid cancer have shown clinical benefit in patients with advanced cancer. Treatmentrelated toxicities occur frequently with these drugs and can be severe or life-threatening. Objective: This review summarizes the role of targeted therapy with MKIs in the management of RRDTC and advanced/metastatic MTC patients, focusing on side-effect profiles of these drugs, with a presentation of several recent patents published in this field. Methods: We review the scientific literature on advanced thyroid cancer and analyze the International Pharmacovigilance database (FAERS, Eudravigilance, and WHO Vigibase) for adverse drug reactions. Results: This systematic analysis highlights the difference in the safety profile of the recent drugs used in the treatment of advanced thyroid cancer and the recent discoveries for diagnosis or treatment of the thyroid cancer. Conclusion: It is essential to investigate the safety profile of recent anticancer drugs for advanced thyroid cancer to allow health professionals to make the best choice for each patient by conducting risk/benefit assessment.
9558 Background: Irinotecan (CPT11) in combination with HAART has been found active in patients with advanced AIDS-related Kaposi’s sarcoma [Vaccher E et al. AIDS 2005]. Dose-limiting toxicity consisted of persistent leukopenia, suggesting the potential for pharmacokinetic interactions between CPT11 and lopinavir boostered with ritonavir, the protease inhibitor component of HAART. Methods: Six HIV-infected patients with advanced Kaposi’s sarcoma were prospectively treated with CPT11 at a dose of 150 mg/m 2 , given as a 90-min infusion on days 1 and 10, in absence and in combination with 400mg/100mg LPV/rtv. Pharmacokinetic parameters of the CPT11, the active metabolite (SN38), its glucoronide derivative (SN-38G), and the APC metabolite were investigated over a 50 h time interval at the first day of chemotherapy cycle. A 2-day LPV/rtv washout was allowed before the evaluation of pharmacokinetics of CPT11 alone. The pharmacokinetics of CPT11 in combination with LPV/rtv was determined at day-10 (paired cross over). Results: The mean (± SD) clearance of CPT11 was found significantly lower when CPT11 was administered in combination with LPV/rtv (13.39±3.39 l/h/m 2 vs 23.55±7.16 l/h/m 2 , p<0.05 for CPT11+ LPV/rtv and CPT11 alone respectively). This was associated with a 94.3% reduction of AUC APC oxidized metabolite and with 2.9 and 1.8-fold increase of SN38 and SN38G AUC, respectively. During the CPT11+ LPV/rtv, the ratio SN38/CPT11 AUC was higher (0.031±0.008 vs 0.019±0.006, p<0.05) while the glucoronidation ratio (the AUC ratio of SN38G and SN38) was found significantly lower (5.50±1.43 vs 9.03±2.49, p<0.05) as compared to the administration of CPT11 alone. Conclusions: This preliminary investigation indicates that CPT11 pharmacokinetics can be strongly influenced by the co-administration of LPV/rtv. This leads to a significant increase of AUC SN38 active metabolite, likely associated to an increase of CPT11 activation and in a reduction of SN38 glucoronidation paths, which may have profound effects on pharmacodynamic of CPT11 when used in combination with LPV/rtv -based HAART. No significant financial relationships to disclose.
Objective Membrane transporters are widely recognized as important determinants of drug disposition and response, generating increasing interest on the pharmacological implications of their genetic variations. The aim of this study was to elucidate the predictive/prognostic role of ATP-binding cassette (ABC) and solute carrier (SLC) protein polymorphisms on irinotecan (FOLFIRI regimen) outcome. Patients and methods A total of 250 White metastatic colorectal cancer patients homogenously treated with a first-line FOLFIRI regimen were genotyped for a panel of variants in five transporter genes. The primary study endpoints were the response rate (partial or complete response), overall survival, and time to progression. Toxicity was considered a secondary endpoint. Irinotecan pharmacokinetic data of 71 patients were used for polymorphism functional analysis. Results Two variants of the ABCG2 (−15622C>T, rs7699188) gene were found to be predictive (P<0.01) of the response rate. High-order relationships of ABC/SLC markers with previously investigated genetic (UGT1A1 polymorphisms) and nongenetic (primary tumor site) factors that helped determine the response rate were highlighted. A prognostic effect of the ABCB1 rs2032582 variant on patient overall survival emerged (P=0.0074). The ABCG2 rs7699788 variant was also seen to be associated with grade 3–4 nonhematological toxicity (P=0.0012). The ABCG2 (−15622C>T, rs7699188) and ABCB1 (rs2032582) polymorphisms were not found to be associated with pharmacokinetic parameters. Conclusion This study showed that ABC/SLC polymorphisms have a crucial contribution toward the FOLFIRI outcome. This could represent a further step toward personalized therapy.
